PubMedCentral-PMC5071137.pdf

Predictors of Non-Escherichia coli Urinary Tract Infection

Nader Shaikh, MD, MPH1, Ellen, R. Wald, MD2, Ron Keren, MD3, Nathan Gotman, MS4, Anastasia Ivanova, PhD4_{, Myra A. Carpenter, PhD}4_{, Marva Moxey-Mims, MD}5_{, and Alejandro} Hoberman, MD1

1_{University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMC, Division}

of General Academic Pediatrics

2_{University of Wisconsin School of Medicine and Public Health, Department of Pediatrics}

3_{Division of General Pediatrics, Center for Pediatric Clinical Effectiveness, Children’s Hospital of}

Philadelphia

4_{University of North Carolina at Chapel Hill, Collaborative Studies Coordinating Center,}

Department of Biostatistics

5_{National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health}

Abstract

We aimed to determine which children are prone to non-Escherichia coli coli UTIs. We included 769 children with UTI. We found that circumcised males, Hispanic children, children without fever, and children with Grade 3–4 VUR were more likely to have a UTI caused by organisms other than E. coli. This information may guide clinicians in their choice of antimicrobial therapy.

Keywords

Vesicoureteral reflux; Escherichia coli

BACKGROUND

The vast majority of cases of community-acquired urinary tract infection (UTI) are caused by E. coli. It may be clinically important to predict which children have UTIs caused by organisms other than E. coli because these organisms differ in their patterns of antimicrobial susceptibility. A recent study found that the organisms other that E. coli were less likely to be susceptible to first generation cephalosporins and nitrofurantoin.1 Furthermore, some guidelines2 have suggested that screening for vesicoureteral reflux (VUR) with a voiding cystourethrogram (VCUG) should, at least in part, be based on whether an organism other than E. coli is recovered.

Our objectives were (1) to determine clinical characteristics that might be useful in differentiating children with UTI caused by E. coli from children with UTIs caused by

HHS Public Access

Author manuscript

Pediatr Infect Dis J

Published in final edited form as:

Pediatr Infect Dis J. 2016 November ; 35(11): 1266–1268. doi:10.1097/INF.0000000000001301.

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organisms other than E. coli, and (2) to understand associations between clinical characteristics, VUR and pathogen type.

Methods

We used data from two prospective, multicenter studies, in which clinical and demographic characteristics were carefully documented, to determine characteristics associated with the type of infecting organism. The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial included 607 children with VUR and the parallel observational Careful Urinary Tract Infection Evaluation (CUTIE) study enrolled 195 children without VUR. We excluded 33 children with missing data (for organism, voiding cystourethrogram, race, ethnicity, antibiotic treatment, or presence of bladder and bowel dysfunction [BBD]), with a resulting analytic sample of 769 children. Methods of the RIVUR and CUTIE studies have been previously reported.3–5 Briefly, the RIVUR trial enrolled children 2 to 71 months of age presenting with a first or second febrile or symptomatic UTI from both primary and subspecialty care settings at clinical trial centers throughout North America. Children who were found to have grades I to IV VUR after their index UTI were enrolled in the RIVUR trial. Children 2 to 71 months of age with a first or second UTI but without VUR were enrolled in the CUTIE study at 3 of the 19 participating RIVUR sites (Pittsburgh, Philadelphia and Washington, DC). In both studies urine samples were collected by catheterization, suprapubic aspiration or by clean void; bag-collected specimens were not permitted.

We used logistic regression models to test the associations between demographic and clinical characteristics and uropathogen. The clinical model included baseline predictors known or easily measured at a clinical visit: age, gender, race, ethnicity, presence of BBD, use of antimicrobials in the preceding 6 months for infections other than UTIs, number of previous UTIs, type of index UTI (febrile vs. afebrile). We included site (grouped into 6 administrative sites) in the model as a covariate, and categorized age as 2–11 months, 12–23 months, 24–35 months, and 36–72 months. In the association model, we added VUR (a characteristic not known without performance of VCUG) to the clinical model. We also considered unadjusted associations with uropathogens for the following symptoms: suprapubic/abdominal/flank pain or tenderness, urinary urgency, urinary frequency, urinary hesitancy, dysuria, and foul-smelling urine.

Results

Of 769 children included, 703 (91%) were female and 596 (78%) were white. Forty-nine percent of the cohort was 2–11 months of age; 699 (91%) had index UTIs caused by E. coli. The 70 children with UTIs caused by organisms other than E. coli incuded 21 (30%) with Proteus species, 16 (23%) with Klebsiella species, 14 (20%) with Enterococcus species, 8 (11%) with Enterobacter species, and 11 with other species. Data regarding the antimicrobial resistance of the organisms isolated from these children have been previously reported.1 Children enrolled in the CUTIE study were older (30% vs. 20% were 36–72 months of age), more likely to be non-white (33% vs. 19%) and Hispanic (20% vs. 12%). Further details regarding the demographic makeup of the sample have previously been reported.

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In the clinical model, circumcised males (OR=5.5, 95% CI=1.8—17.1, p=0.003, Table) and Hispanic children (OR=2.3, 95% CI=1.1—4.6, p=0.02) were more likely to have infection caused by pathogens other than E. coli compared with females and non-Hispanic children, respectively (Table). Children without fever were also more likely to have infections caused by organisms other than E. coli (OR=2.8, 95% CI=1.2—6.6, p=0.02). Pathogen type was similar with respect to age, race, presence of BBD, duration of UTI symptoms before presentation, number of previous UTIs, and number of courses of antimicrobials received in the preceding 6 months for conditions other than UTI.

In the association model, children with grade 3–4 VUR had higher odds of non-E.coli infections (OR=2.2, 95% CI=1.2—4.1, p=0.01) compared with children with grade 1–2 VUR (Table). Children with no VUR had a similar odds of non-E.coli infections compared to children with grade 1–2 VUR. In the association model, odds ratios noted in the clinical model were largely unchanged. Children 4 months or younger with failure to thrive had a higher percentage of non-E.coli infections than other children 4 months or younger (24% vs. 11%). Primary pathogens were similar for other individual symptoms.

Discussion

We found that circumcised males, children with grade III or IV VUR, Hispanic children and children without fever were more likely to have UTI caused by organisms other than E. coli. The association between gender and organism type has been previously reported.6,7 Previous studies have also reported the association between VUR and uropathogen.8,9 High-grade VUR may be necessary for generally less virulent organisms, which lack adhesins prevalent among E. coli starins, to ascend to the kidney. The association between Hispanic ethnicity and non-E. coli pathogens is novel and may be due to differences in genes involved with susceptibility to UTIs. Fever with infections caused by E. coli may be related to the organism’s enhanced ability to ascend into the kidney.

Approximately one quarter of circumcised males and one quarter of afebrile children had infections caused by organisms other than E. coli. As a group, non-E. coli species are more likely to be resistant to first generation cephalosporins and nitrofurantoin.1 Accordingly, if these data are replicated, clinicians may want to avoid using first-line agents for the treatment of UTIs in these subgroups.; second or third generation cephalosporins would be the preferred agents.

Children with UTIs caused by organisms other than E. coli were twice as likely to have high-grade VUR (Grade III and IV), which is consistent with prior studies.8,9

The main limitation of this study is that the children we included are not likely

representative of all children with UTI because tbecause a relatively large proportion of children had VUR. Nevertheless, after adjusting for VUR, circumcised males and afebrile children had higher rates of infection by organisms other than E. coli.

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References

1. Shaikh N, Hoberman A, Keren R, et al. Predictors of Antimicrobial Resistance among Pathogens Causing Urinary Tract Infection in Children. J Pediatr. 2016; 171:116–121. [PubMed: 26794472] 2. National Institute for Health and Care Excellence. Urinary Tract Infection in Children: diagnosis,

treatment, and long term management. [Accessed April 30, 2015] http://www.nice.org.uk/ nicemedia/live/11819/36028/36028.pdf.

3. Hoberman A, Greenfield SP, Mattoo TK, et al. Antimicrobial prophylaxis for children with vesicoureteral reflux. The New England journal of medicine. 2014; 370:2367–2376. [PubMed: 24795142]

4. Keren R, Carpenter MA, Hoberman A, et al. Rationale and design issues of the Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) study. Pediatrics. 2008; 122(Suppl 5):S240–S250. [PubMed: 19018048]

5. Keren R, Shaikh N, Pohl H, et al. Risk Factors for Recurrent Urinary Tract Infection and Renal Scarring. Pediatrics. 2015; 136:e13–e21. [PubMed: 26055855]

6. Edlin RS, Shapiro DJ, Hersh AL, Copp HL. Antibiotic resistance patterns of outpatient pediatric urinary tract infections. J Urol. 2013; 190:222–227. [PubMed: 23369720]

7. Saperston KN, Shapiro DJ, Hersh AL, Copp HL. A comparison of inpatient versus outpatient resistance patterns of pediatric urinary tract infection. J Urol. 2014; 191:1608–1613. [PubMed: 24679887]

8. Honkinen O, Jahnukainen T, Mertsola J, Eskola J, Ruuskanen O. Bacteremic urinary tract infection in children. Pediatr Infect Dis J. 2000; 19:630–634. [PubMed: 10917221]

9. Jantunen ME, Siitonen A, Ala-Houhala M, et al. Predictive factors associated with significant urinary tract abnormalities in infants with pyelonephritis. Pediatr Infect Dis J. 2001; 20:597–601. [PubMed: 11419502]

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Predictors of infection with an or

g

anism other than

E. coli

; unadjusted, clinical

* and association * models

Unadjusted Clinical Model Association model n/N % Non-E. coli

Odds ratio (CI)

P

Odds ratio (CI)

*

P

*

Odds ratio (CI)

*

P

*

Age (months) 2–11

34/374 9 Ref Ref Ref 12–23 5/136 4

0.4 (0.2, 1.0)

0.05

0.4 (0.2, 1.2)

0.10

0.4 (0.2, 1.2)

0.11

24–35

14/89

16

1.9 (1.0, 3.7)

0.07

1.6 (0.7, 3.7)

0.29

1.6 (0.7, 3.8)

0.27

36–72

17/170

10

1.1 (0.6, 2.1)

0.74

0.8 (0.2, 2.6)

0.66

0.7 (0.2, 2.5)

0.61

Race White

58/596 10 Ref Ref Ref Non-White 12/173 7

0.7 (0.4, 1.3)

0.26

0.6 (0.3, 1.1)

0.11

0.6 (0.3, 1.2)

0.12

Gender Female

58/703 8 Ref Ref Ref Uncircumcised Male 7/45 16

2.1 (0.9, 4.8)

0.10

1.6 (0.6, 4.6)

0.35

1.7 (0.6, 4.8)

0.35

Circumcised Male

5/21

24

3.5 (1.2, 9.8)

0.02

5.5 (1.8, 17.1)

0.003

5.3 (1.7, 16.9)

0.005

Ethnicity Non-Hispanic

54/663 8 Ref Ref Ref Hispanic 16/106 15

2.0 (1.1, 3.7)

0.02

2.3 (1.1, 4.6)

0.02

2.4 (1.2, 4.8)

0.02 Bladder Bo wel Dysfunction No 10/84 12 Ref Ref Ref Y es 10/95 11

0.9 (0.3, 2.2)

0.77

0.8 (0.3, 2.2)

0.67

0.8 (0.3, 2.1)

0.65

Not toilet trained

50/590

8

0.7 (0.3, 1.4)

0.30

0.7 (0.2, 2.4)

0.58

0.6 (0.2, 2.1)

0.45

Courses of antimicr

obials in the

pr

eceding 6 months

0 31/399 8 Ref Ref Ref 1 22/229 10

1.3 (0.7, 2.2)

0.43

1.3 (0.7, 2.5)

0.36

1.3 (0.7, 2.5)

0.38

≥2

17/141

12

1.6 (0.9, 3.0)

0.13

1.6 (0.8, 3.2)

0.16

1.8 (0.9, 3.4)

0.11

Number of pr

evious UTIs 0 60/700 9 Ref Ref Ref 1 10/69 14

1.8 (0.9, 3.7)

0.11

1.6 (0.7, 3.5)

0.28

1.5 (0.7, 3.4)

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Odds ratio (CI)

P

Odds ratio (CI)

*

P

*

Odds ratio (CI)

*

P

*

VUR Grade No VUR

12/186

6

0.9 (0.4, 1.8)

N/A

*

1.2 (0.5, 2.9)

0.67

Grades I or II

23/314

7

Ref

Grades III or IV

35/269

13

1.9 (1.1, 3.3)

N/A

*

2.2 (1.2, 4.1)

<0.01 F ev er No 11/46 24

3.8 (1.8, 8.0)

0.0004

2.8 (1.2, 6.6)

0.02

3.3 (1.4, 7.8)

0.008 Y es 49/644 8 Ref Ref Ref Unkno wn 10/79 13

1.8 (0.9, 3.6)

0.13

1.4 (0.6, 3.3)

0.43

1.4 (0.6, 3.3)

0.44

Site Pittsb

ur gh 20/273 7 Ref Ref Ref Philadelphia 6/89 7 0.9(0.4, 2.4) 0.85

1.0 (0.4, 2.7)

0.98

1.0 (0.4, 2.8)

0.94

W

ashington DC

4/77

5

0.7 (0.2, 2.1)

0.52

0.6 (0.2, 1.9)

0.35

0.5 (0.2, 1.8)

0.30

Baltimore

7/78

9

1.3 (0.5, 3.1)

0.63

1.2 (0.4, 3.1)

0.76

1.0 (0.3, 2.7)

0.94

Michig

an

14/106

13

1.9 (0.9, 4.0)

0.08

2.1 (0.9, 4.7)

0.08

1.7 (0.7, 4.2)

0.23 Ne w Y ork 19/146 13

1.9 (1.0, 3.7)

0.06

1.8 (0.9, 3.6)

0.13

1.6 (0.7, 3.6)

0.27

Ref, reference cate

gory

.

* The clinical model adjusted for age, race, ethnicity

, gender

, BBD, fe

v

er

, site, number of pre

vious UTIs, and pre

vious antibiotic. The association model adjusted for all of the v

ariables in the clinical model

plus v